Advances in retinal imaging are fundamental to the recent paradigm shifts in the diagnosis and management of ocular disease and in the understanding of the pathogenesis of these disorders.1 Evaluation of a broad spectrum of various types of retinal images is essential to modern ophthalmic practice and has become the optimal standard of care for successful management of retinal disorders. There are a wide range of retinal technologies that can acquire two-dimensional or three-dimensional en face and cross-sectional images, some of which are depth-resolved, that may provide information about anatomic structure, function, or dynamic vascular flow. Common imaging modalities include color fundus photography; near-infrared reflectance (NIR); fundus autofluorescence;2,3 fluorescein angiography; indocyanine green angiography;4 scanning-laser ophthalmoscopy with2,5 and without adaptive optics;6,7 optical coherence tomography (OCT);8–10 and, more recently, OCT angiography (OCTA).11,12 Each modality has unique advantages and limitations and requires a specific skill set for optimal application and interpretation. When analyzed together, different imaging modalities can increase diagnostic sensitivity and specificity. Recently, the term “multimodal imaging” has been used in an increasing number of clinical reports, emphasizing the importance of combining a variety of imaging modalities. However, no specific definition of this terminology has been established in ophthalmology.
The term multimodal imaging has been used in a variety of medical specialties such as oncology,13 radiology14,15, and cardiology long before expansion of the term to describe ophthalmic imaging techniques. It has been defined as the combination of imaging modalities to provide improved preclinical assessment, diagnostics, and therapeutic monitoring.16 The Cardiology Imaging Council defined multimodal imaging as “the efficient integration of two or more methods of imaging to improve the ability to diagnose, guide therapy, or predict outcomes.”17
In ophthalmology, it is uncommon for clinicians to rely on a single imaging modality to determine diagnosis and therapy. Instead most choose more than one technique for a given clinical situation. To be successful, one must have knowledge of the potential benefits and shortcomings of each imaging modality to know which is ideal for any given clinical situation. Because there is considerable overlap in the information provided by certain imaging modalities, it is important for clinicians to choose the minimum numbers of studies needed to accomplish the clinical goal and to avoid unnecessary cost and burden to the patient. In ophthalmology, most reports classify multimodal imaging as the combination of en face fundus imaging, en face dye-base angiography, cross-sectional and/or en face OCT, and possibly autofluorescence when relevant to evaluate a specific disease.18–22 Analyzing images from multiple imaging modalities can be used as a preliminary step in understanding new technologies, such as when comparing dye-based angiography to OCTA.23
We propose a definition of multimodal imaging as it applies to the practice of ophthalmology: To comprise the use of more than one technological system to acquire images, concurrently or at a short period of time, that complement one another for the purpose of diagnosis, prognostication, management, and monitoring of disease. Thus, all modalities can analyze a specific structure unequivocally. This may include hybrid devices that can simultaneously perform more than one imaging modality. For example, a fundus camera may provide color images of the retina; however, if excitation and emission filters are added to the camera to obtain fundus autofluorescence imaging, this device could be considered a multimodal platform. Similarly, commercial systems that combine OCTA with a corresponding structural OCT B-scan of the retina utilize different technological platforms and provide contrasting anatomical (blood flow versus static tissue layers) information and could also be considered a multimodal approach. Therefore, when the retina is imaged by different technological systems (whether the machine is changed or not), providing a different image of the fundus, this would constitute, in the authors' consensus, a multimodal-imaging platform.
There are many clinical situations in which the application of a multimodal approach can enhance the evaluation and understanding of retinal disease. Multimodal retinal imaging has vastly expanded the phenotypic spectrum of hereditary retinal diseases and has expanded our pool of genetic diagnoses. The spectrum of cone dystrophies is highly diverse, and mutational diagnosis is best guided by multimodal imaging. Patients with a golden tapetal fundus by standard photography, for example, and associated with outer macular atrophy on spectral-domain OCT (SD-OCT) and bull's-eye atrophy on fundus autofluorescence should be screened for a cone-rod dystrophy or RPGR mutation (Figure 1). However, eyes with only a small central ellipsoid defect on SD-OCT, and those with normal fundus photography and autofluorescence, should be genetically screened for an RP1L1 mutation.24–26
Multimodal imaging of a 42-year-old man with bilateral golden tapetal fundus secondary to X-linked progressive cone-rod dystrophy. (A) Color fundus photography shows a golden tapetal-like sheen of the fundus. (B) Fundus autofluorescence. Note the central ring of hyperautofluorescence consistent with a bull's-eye maculopathy. (C) Optical coherence tomography. Outer macular atrophy with severe loss of the photoreceptors and the inner and outer segments are noted in the fovea (yellow dotted line).
Multimodal imaging has also led to the identification of macular disorders that affect the middle retina and are associated with deep retinal capillary ischemia. Paracentral acute middle maculopathy lesions have only recently been identified as a result of the paracentral lesions best detected with NIR and SD-OCT. More recently, OCTA has confirmed the presence of deep retinal capillary ischemia associated with these lesions.27–29 Multimodal imaging has also led to the very important understanding of the pachychoroid spectrum that includes pachychoroid pigment epitheliopathy (Figure 2),30 pachychoroid neovasculopathy,31 and polypoidal choroidal vasculopathy,32–34 which are additional important entities we have added to the clinical spectrum of retinal disease due to multimodal imaging.
Multimodal imaging of a 63-year-old woman with pachychoroid pigment epitheliopathy. (A) Color fundus photography shows nonspecific perifoveal mottling of the retinal pigment epithelium (RPE), previously attributed to non-neovascular age-related macular degeneration. (B) Near-infrared reflectance (NIR) highlights the RPE alterations. (C, D) Enhanced-depth imaging optical coherence tomography (EDI-OCT) shows large, dilated choroidal pachyvessels directly beneath the RPE abnormalities with loss of Sattler's layer. Multimodal imaging with the combination of color photography, NIR, and EDI-OCT highlights the RPE abnormalities and illustrates a thickened choroid with dilated pachyvessels consistent with a diagnosis of pachychoroid pigment epitheliopathy.
Application of a multimodal approach challenges the retinologist to continually develop experience and skill utilizing and interpreting multiple technological systems and constantly updating this skill set as advanced systems are introduced to the clinical arena. These advancements promote a continued and progressive insight and understanding of the mechanisms of retinal disease. Further multimodal imaging has steadily provided an ever-expanding database of knowledge that has improved our diagnosis and management of retinal disease and fostered optimal clinical care of our patients.
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- Yannuzzi LA, Slakter JS, Sorenson JA, Guyer DR, Orlock DA. Digital indocyanine green videoangiography and choroidal neovascularization. Retina. 1992;12(3):191–223. doi:10.1097/00006982-199212030-00003 [CrossRef]
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- Coscas GJ, Lupidi M, Coscas F, Cagini C, Souied EH. Optical coherence tomography angiography versus traditional multimodal imaging in assessing the activity of exudative age-related maculatr degeneration: a new diagnostic challenge. Retina. 2015;35(11):2219–2228. doi:10.1097/IAE.0000000000000766 [CrossRef]
- Sato T, Suzuki M, Ooto S, Spaide RF. Multimodal imaging findings and multimodal vision testing in neovascular age-related macular degeneration. Retina. 2015;35(7):1292–1302. doi:10.1097/IAE.0000000000000505 [CrossRef]
- Moysidis SN, Koulisis N, Ameri H, et al. Multimodal imaging of geographic areas of retinal darkening. Retin Cases Brief Rep. 2015;9(4):347–351. doi:10.1097/ICB.0000000000000231 [CrossRef]
- Roybal CN, Sanfilippo CJ, Nazari H, et al. Multimodal imaging of the retina and choroid in systemic amyloidosis. Retin Cases Brief Rep. 2015;9(4):339–346. doi:10.1097/ICB.0000000000000215 [CrossRef]
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Jay S. Duker, MD, can be reached at New England Eye Center at Tufts Medical Center, 260 Tremont Street, Biewend Building, 9 – 11th Floor, Boston, MA 02116; 617-636-7950; fax: 617-636-4866; email:
Disclosures: Dr. Novais is a researcher supported by CAPES Foundation, Ministry of Education of Brazil, Brasilia, DF, Brazil; Dr. Freund is a consultant to and receives honorarium from Optovue, Genentech, Optos, ThromboGenics, Ohr Pharmaceutical, and Heidelberg Engineering. Dr. Duker is a consultant for and receives research support from Carl Zeiss Meditec, OptoVue, and Topcon Medical Systems and has stock in Hemera Biosciences, EyeNetra, and Ophthotech Corp. The remaining authors report no relevant financial disclosures.
Imaging Modalities in Retina
Color Fundus Photography
||Flood light illumination without the use of filters. Color image of the fundus, traditionally 30° or 50°, although wide-field color fundus photography also available. Provides real color representation of disease.
||Flood light illumination with the use of filters. Aids the visualization of anatomic structures and disease features at different levels within the retina. Red-free: Fundus photography images taken with flood illumination through a green filter captures excitation green light and highlights the inner retina. Green-free: fundus photography with a filter that captures long-wavelength excitation light, thereby highlighting deeper structures such as the RPE and the choroid.
Scanning Laser Ophthalmoscope (SLO)
||Excitation laser beam in a raster pattern illuminates successive elements of the retina. May produce images with higher contrast than standard flood-illuminated fundus cameras. It can be used with various retinal-imaging systems, including near-infrared reflectance, FA, ICGA, and FAF. Adaptive optics SLO: enable the dynamic correction of optical aberrations. The wavefront sensor measures eye aberrations, and the spatial light modulator or a deformable mirror compensates for these aberrations. The adaptive optics system is confocal, enabling creation of en face images. These high-resolution images show individual cone photoreceptor structures, which can be helpful in cone-loss diseases such as MacTel, retinal dystrophies, and many others.
Near-Infrared Reflectance (NIR) SLO
||SLO provides a laser source and different excitation wavelengths (blue, green, infrared) can be administered. These images can be viewed individually or as a composite (ie, pseudocolor fundus image). NIR imaging is a method that uses the near-infrared region of the electromagnetic spectrum (from about 700 nm to 2,500 nm). The NIR with the SLO utilizes a 78-nm wavelength that penetrates more easily through the optical media and has a reduced absorption and increased reflection by melanin and hemoglobin when compared with light of wavelengths shorter than 585 nm. Since the wavelength used is barely visible, this technique is well-tolerated by patients. Blue and green reflectance provide information regarding the inner retina. Infrared reflectance will highlight deeper structures such as the RPE, choroid.
Multicolor Scanning Laser Imaging
||Based on confocal scanning ophthalmoscopy, which utilizes several wavelengths of laser to gather diagnostic information from different layers of the retina. Provides a high-contrast image that can potentially identify pathology that is difficult to detect on corresponding color fundus photographs (ie, media opacity).
Fundus Autofluorescence (FAF)
||Excitation and emission filters in traditional fundus-based or SLO cameras are used to capture the inherent fluorescent characteristics of ocular tissues. FAF excitation wavelength may vary from 300 nm to 600 nm, and emission filters are typically greater than 500 nm. FAF is used to analyze RPE function and specifically lipofuscin, a byproduct of photoreceptor outer segments metabolism. Short-wavelength or “blue light” FAF (excitation 488 nm) imaging allows topographic mapping of lipofuscin distribution in the RPE in vivo. The absence of RPE lipofuscin, due to atrophy, shows a severely reduced signal, appearing dark. There is greater absorption by macular luteal pigment seen with blue light FAF than that obtained with longer wavelengths. Near-infrared FAF (excitation 787 nm) visualize the distribution of melanin, a fluorophore of the RPE cells and choroid.
||Can be performed using a flood-illuminated fundus camera incorporating band-pass excitation and emission filters, or using SLO devices that can achieve better resolution and contrast. Circulating dye molecules absorbs the light and emits light with a different wavelength. A barrier filter blocks any reflected light so that the images capture only light emitted from the dye. FA: visualization of retinal vessels integrity, perfusion, and leakage. ICGA: enhanced visualization of the choroidal circulation.
Optical Coherence Tomography (OCT)
||OCT applies the property of interferometry to analyze reflected light waves from the retina, creating cross-sectional images of the retina with histopathological grade resolution. Initial algorithms based on time-domain OCT technology had limited speed (400 A-scans/s) and resolution (10 µm to 15 µm); however, with the evolution to spectral-domain OCT technology, greater speed (20,000 to 70,000 A-scans/s) and better resolution (5 µm to 6 µm) can be achieved. More recently with swept-source OCT technology, augmented-depth visualization became possible. This technology has become the gold-standard imaging modality to assess macular edema and its response to treatment and can localize the level of retinal loss and atrophy. This technology can generate en face images for a depth-resolved analysis of the retinal architecture permitting layer by layer analysis of the retina.
||Generates depth-resolved analysis of the retinal and choroidal vasculature, using phase- or amplitude-based OCT technology. This technology can also generate en face intensity images for an overall analysis of the microvasculature, and cross-sectional views for blood flow evaluation at a depth-resolved level without the use of intravenous dye. Identification of the microvascular morphology of neovascular lesions in AMD, and their response to therapy, may be performed with OCT angiography. Analysis of the deep retinal capillary plexus in retinal vascular disease to assess for ischemia also expedited with OCT angiography.
||Sound waves are generated and reflected back to the transducer by tissue in its path. When the sound wave returns, a piezo-electric crystal in the transducer vibrates, resulting in electrical impulses that are translated into an image. A-scan (time-amplitude scan): sound waves are converted into spikes that correspond with tissue interface zones. B-scan, or brightness amplitude scan: sound waves are collected by the transducer produces a corresponding image. Ultrasonography is useful for the dynamic evaluation of the posterior pole, particularly in eyes with opaque media.
Imaging Modalities in Retina